Scientists at Harvard and at Sirtris Pharmaceuticals keep defying conventional wisdom, mounting an ever-stronger case that lifespan can be extended by taking a pill.

In the journal Nature published today, researchers report that three compounds invented by Sirtris have succeeded in activating cellular defenses that slow diseases of aging in the same way associated with resveratrol, a naturally occurring chemical found in red wine.

The difference is that Sirtris's synthetic compounds are 1,000 times as potent as the resveratrol in wine. This solves a big drawback with the naturally occurring chemical—wine contains such minute quantities that a person would have to drink hundreds of bottles a day to see any significant benefit.

The potent new pills mimic resveratrol in mice by activating the SIRT-1 gene, which appears to trigger a process called caloric restriction. In many organisms, that process acts to slow down aging and ramp up cellular defenses in the face of a reduced diet during times of scarce food supplies. Sirtris's new compounds, however, act without the little critters having to reduce their diet.

In past experiments, many of them conducted by Harvard pathologist and Sirtris cofounder David Sinclair, resveratrol has increased the lifespan of mice up to 24 percent, and other simpler organisms such as yeast up to 59 percent. In November 2006, Sinclair and Sirtris scientists that resveratrol could reduce the impact of a high fat diet, increase stamina two fold and significantly extend lifespan of mice.

Skeptics have long claimed that aging is too complex to be regulated by a small number of genes, though Sinclair and other leading longevity scientists such as Leonard Guarente of the Massachusetts Institute of Technology and Cynthia Kenyon of the University of California at San Francisco keep refining and supporting their argument that it is.

Investors have believed the Sirtris story enough to pony up $103 million in private rounds and $63 million in an IPO last May. Sirtris' stock today has risen as much as 6 percent—roughly twice the rise in the S&P 500 index.

The current paper does not target longevity specifically, but demonstrates that Sirtris's pills may slow a major disease of aging, diabetes type II, which afflicts 18 million Americans.

The pills improved insulin sensitivity, lowered plasma glucose levels, and increased the function of mitochondria, the powerhouse of the cell that is associated with healthy and long-living cells.

"In this study, these novel drug candidates improved insulin sensitivity, which could unlock a new approach to treating type 2 diabetes," Christoph Westphal said in an email. Westphal is C.E.O. and a cofounder of Sirtris, and a co-author of the study. The lead author is Jill Milne, senior director of biology at Sirtris.

This past May, the company started human trials using a super-potent version of resveratrol, and so far the drug has passed muster. The synthetic compounds are both more potent and more stable chemically.

They also are better candidates for Food and Drug Administration approval since in many cases a synthetic compound concocted in a lab can be more consistently manufactured and standardized for doses than products based on a natural compound.

Westphal says that the three "New Drug Entities" described in today's paper will begin human trials in the first half of 2008. Then we can find out if these new super-drugs for making us stay young and healthy longer will work in you and me - proof that is still years away, though the intriguing possibility just moved a step closer.

by David Ewing Duncan

_{Illustration by: Leif Parsons}